KR100352196B1 - Sepsis and septic shock medication - Google Patents
Sepsis and septic shock medication Download PDFInfo
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- KR100352196B1 KR100352196B1 KR1019940011258A KR19940011258A KR100352196B1 KR 100352196 B1 KR100352196 B1 KR 100352196B1 KR 1019940011258 A KR1019940011258 A KR 1019940011258A KR 19940011258 A KR19940011258 A KR 19940011258A KR 100352196 B1 KR100352196 B1 KR 100352196B1
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- component
- inhibitor
- thrombin
- sepsis
- receptor
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- A—HUMAN NECESSITIES
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- A61K38/58—Protease inhibitors from animals; from humans from leeches, e.g. hirudin, eglin
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
본 발명은 패혈증 및 패혈증성 쇼크의 치료 및 예방을 위한 이성분 시스템 (two-component system; 여기서, 이성분들은 서로 협력하여 작용한다), 두 성분을 함유한 약제 및 포장 단위, 및 이들의 제조방법에 관한 것이다.The present invention relates to a two-component system for treating and preventing sepsis and septic shock, wherein the two components work in concert with each other, a pharmaceutical and packaging unit containing two components, and a method of preparing the same. It is about.
Description
본 발명은 패혈증 및 패혈증성 쇼크 치료 및 예방용 이성분 시스템(two-component system; 여기서, 이 성분들은 서로 협력하여 작용한다), 두 성분을 함유한 약제 및 포장 단위, 및 이들의 제조방법에 관한 것이다.The present invention relates to a two-component system for treating and preventing sepsis and septic shock (these components work in concert), pharmaceutical and packaging units containing two components, and methods for their preparation will be.
항생제 치료에서의 발전에도 불구하고, 세균성 패혈증은 집중적인 치료에 주요한 문제점이 있고, 패혈증성 쇼크에 의한 사망률은 50 내지 70%로 여전히 너무도 높다.Despite advances in antibiotic therapy, bacterial sepsis is a major problem for intensive treatment, and mortality due to septic shock is still too high at 50-70%.
패혈증에 걸린 환자에서 나타난 것은 특히 그람-네가티브 세균이며, 감염의 장재적 근원은 위장관 및 배설 요로 및 기도 및 또한 감염된 상처 및 화상이다.It is especially Gram-negative bacteria that appear in patients with sepsis, and the underlying source of infection is the gastrointestinal tract and excretory tract and airways and also infected wounds and burns.
그람-네가티브 세균의 세포벽으로부터 내독소(지다당류, LPS)가 방출된 다음, LPS는 지다당류-결합 단백질(LPB)에 결합하고, LPS/LPB 복합체는 CD14 수용체를 통해 대식세포에 결합한다. 이런 방식으로 자극된 대식세포는 특히 TNFα, 인터로이킨(interleukin) 1 및 인터로이킨 6 등과 같은 시토킨을 분비한다. 과립구는 이들 조정제에 의해 활성화되고, 내피는 항응고성 상태로부터 응혈촉진성 상태로 전환된다. 트롬보플라스틴의 발현의 결과로서 응고의 외부 경로는 인자 VII/트롬보플라스틴 복합체의 형성에 의해 활성화된다. 이것은 프로트롬비나제 복합체를 활성화시킨 다음, 불활성 프로트롬빈을 효소적으로 활성인 트롬빈(인자 IIa)으로 전환시킨다. 피브로노겐이 피브린으로 분해되어 말단 혈관상에서 마이크로트롬비(만연된 내혈관 응혈이상증, DIC)의 형성을 유발한다. 혈관상을 통한 혈액 흐름이 감소되어, 산소 공급이 부족하게 되고, 결과적으로 기관 기능장애(다발성 기관 부전)가 생긴다. 한편으로는, LPS는 내인성 응혈 시스템의 접촉 활성화에 의해 직접적으로 인자 XII(하게만(Hagemann) 인자)를 활성화시킬 수 있으므로, 또한 칼리크레인/키닌 시스템 및 보체 시스템을 활성화시킬 수 있다. 브레디키닌의 형성은 혈압을 강하시켜, 또한 패혈증성 쇼크를 일으킨다.After endotoxin (liposaccharide, LPS) is released from the cell wall of gram-negative bacteria, LPS binds to lipopolysaccharide-binding protein (LPB) and LPS / LPB complex binds to macrophages through CD14 receptor. Macrophages stimulated in this way secrete cytokines such as TNFα, interleukin 1 and interleukin 6, among others. Granulocytes are activated by these modulators and the endothelium is converted from an anticoagulant state to a coagulant state. As a result of the expression of thromboplastin the external pathway of coagulation is activated by the formation of the Factor VII / thromboplastin complex. This activates the prothrombinase complex and then converts inactive prothrombin to enzymatically active thrombin (Factor IIa). Fibronogen decomposes into fibrin, causing the formation of microthrombi (a prevalent intravascular coagulopathy, DIC) on terminal vessels. Blood flow through the blood vessels is reduced, resulting in a lack of oxygen supply, resulting in organ dysfunction (multiple organ failure). On the one hand, LPS can activate factor XII (Hagemann factor) directly by contact activation of the endogenous coagulation system, thus also activating the kallikrein / kinin system and the complement system. The formation of bradykinin lowers blood pressure and also causes septic shock.
패혈증을 치료하기 위해, LPS에 대한 항체외에도 TNF 또는 인터로이킨 1에 대한 항체, 길항제 또는 가용성 수용체를 사용하는 것이 공지되어 있다.To treat sepsis, it is known to use antibodies, antagonists or soluble receptors against TNF or interleukin 1 in addition to antibodies against LPS.
마이크로르롬비의 형성은 응혈 시스템의 주요한 프로테아제인 트롬빈을 불활성화시킴에 의해 억제시킬 수 있다.Formation of microrrombi can be inhibited by inactivating thrombin, a major protease in the coagulation system.
안티트롬빈 III은 트롬빈의 생리학적 억제제이고, 58kD의 분자량을 갖는 안티트롬빈 III 단백질은 사람 혈장으로부터 분리할 수 있다. 안티트롬빈 III은 트롬빈과 화학량론적 비율로 반응하고, 이 반응 속도는 설페이트화된 다당류, 특히 헤파린에 의해 크게 증가한다.Antithrombin III is a physiological inhibitor of thrombin, and antithrombin III protein with a molecular weight of 58 kD can be isolated from human plasma. Antithrombin III reacts with thrombin in a stoichiometric ratio, and this reaction rate is greatly increased by sulfated polysaccharides, in particular heparin.
활성 안티트롬빈 III의 혈장 수준에서의 두드러진 저하가 패혈증 및 패혈증성 쇼크에서 관찰되며, 한편으로는 소비(트롬빈-안티트롬빈 복합체 형성)가 증가되며, 다른 한편으로는 다형핵 과립구에서 분비된 세린 프로테아제, 특히 엘라스타제에 의한 단백질 분해성 변성이 증가된다.A marked decrease in plasma levels of active antithrombin III is observed in sepsis and septic shock, on the one hand increased consumption (thrombin-antithrombin complex formation), on the other hand, serine proteases secreted from polymorphonuclear granulocytes, In particular, proteolytic degeneration caused by elastase is increased.
안티트롬빈(III) 대체물을 패혈증에 사용할 수 있다는 것이 공지되어 있다[참조: B. Blauhut et al., Thromb. Res. 39, 81-89, 1985].It is known that antithrombin (III) replacements can be used for sepsis. See B. Blauhut et al., Thromb. Res. 39, 81-89, 1985].
히루딘은 또다른 매우 특이적인 트롬빈 억제제이다. 히루딘은 또한 실험적 패혈증에서 활성을 갖는다는 것이 입증되었다(참조. H. Hoffmann et al., Am. Rev Respir, Dis. 142, 782-788, 1990).Hirudin is another very specific thrombin inhibitor. Hirudine has also been demonstrated to be active in experimental sepsis (see H. Hoffmann et al., Am. Rev Respir, Dis. 142, 782-788, 1990).
본 발명에 이르러, 본 발명의 두 화합물은 패혈증으로 인한 치사율을 감소시키고 생존 시간을 연장한다는 것이 발견되었다.It has been found that the two compounds of the present invention reduce mortality due to sepsis and prolong survival time.
놀랍게도, 안티트롬빈을 응혈 시스템에 대해 작용하지 않는 물질과 배합함으로써 패혈증의 안티트롬빈 치료를 향상시킬 수 있고, 이러한 배합은 패혈증 및 패혈증성 쇼크에서 치사율을 더욱 감소시킨다는 것이 본 발명에서 밝혀졌다.Surprisingly, it has been found in the present invention that combining antithrombin with substances that do not act on the coagulation system can improve antithrombin treatment of sepsis, which combination further reduces mortality in sepsis and septic shock.
적합한 트롬빈 억제제의 예는 사람 혈장으로부터 또는 재조합으로 제조된 안티트롬빈 III(AT III) 및 트롬빈-억제 활성을 갖는 이의 돌연변이체, 천연 또는 재조합으로 제조된 히루딘 및 트롬빈-억제 활성을 갖는 히루딘의 돌연변이체, 트롬빈-억제 효과가 뛰어난 화학적으로 제조된 물질인 합성 트롬빈 억제제이다.Examples of suitable thrombin inhibitors include antithrombin III (AT III) prepared from human plasma or recombinantly and mutants thereof having thrombin-inhibiting activity, hirudin with natural or recombinant production and hirudin with thrombin-inhibiting activity. Mutant, a synthetic thrombin inhibitor, which is a chemically manufactured substance with excellent thrombin-inhibiting effect.
안티트롬빈 성분과 배합하기에 적합한 화합물들은 시토킨의 형성, 방출, 혈장 및 조직 수준, 및 수용체 결합에 영향을 주는 물질 외에도 보체의 억제제 및 칼리크레인/키닌 시스템의 억제제이다.Compounds suitable for combination with the antithrombin component are inhibitors of complement and inhibitors of the kallikrein / kinin system in addition to substances affecting cytokine formation, release, plasma and tissue levels, and receptor binding.
적합한 물질은 시토킨의 억제제, 길항제 또는 가용성 수용체 또는 시토킨 수용체의 길항제, 바람직하게는 시토킨 TNF(종양 괴사 인자) 및 IL-1의 길항제들이거나, 이들 물질과 항체의 Fc 잔기의 융합 단백질이다.Suitable substances are inhibitors of cytokines, antagonists or antagonists of soluble receptors or cytokine receptors, preferably antagonists of cytokine TNF (tumor necrosis factor) and IL-1, or are fusion proteins of these substances with Fc residues of antibodies .
적합한 시토킨 억제제 및 시토킨 수용체 또는 길항제의 예는, 인터로이킨 1의 생물학적 활성을 억제하는 물질, 예를 들어, 재조합으로 제조된 가용성 IL-1 수용체 또는 재조합으로 제조된 IL-1 수용체, 또는 IL-1 수용체를 함유한 Fc-융합 단백질, IL-1의 길항제, 즉 어떠한 신호도 야기시키지 않는 수용체에 결합하는 It-1-유형 폴리펩타이드, 종양 괴사 인자(TNF)의 생물학적 활성을 억제하는 물질, 예를 들어, 재조합으로 제조된 가용성 TNF 수용체, 재조합으로 제조된 TNF 수용체 또는 TNF 수용체를 함유한 Fc-융합 단백질, TNF의 길항제, 즉 어떠한 신호를 야기시키지 않는 수용체에 결합하는 TNF 유형 폴리펩타이드, 또는 인터로이킨-10 수용체에 결합하여 이 부위에서 신호를 야기하는 재조합으로 제조된 IL-10 또는 이의 돌연변이체이다. 보체 또는 칼리클레인의 적합한 억제제의 예는 사람 혈장으로부터 정제되거나 재조합으로 제조된 C1 에스테라제 억제제(C1INH), 및 효소-억제 활성을 갖는 이의 돌연변이체, 보체-억제 효과가 뛰어난 화학적으로 제조된 물질인 합성 보체억제제, 천연 또는 재조합으로 제조된 아프로티닌, 또는 칼리의레인-억제 돌연변이체, 또는 칼리크레인-억제 효과가 뛰어난 화학적으로 제조된 물질인 합성 칼리크레인 억제제이다.Examples of suitable cytokine inhibitors and cytokine receptors or antagonists include substances that inhibit the biological activity of interleukin 1, eg, recombinantly produced soluble IL-1 receptors or recombinantly produced IL-1 receptors, or IL Fc-fusion proteins containing the -1 receptor, antagonists of IL-1, that is, It-1-type polypeptides that bind to receptors that do not cause any signal, substances that inhibit the biological activity of tumor necrosis factor (TNF), For example, a recombinantly produced soluble TNF receptor, a recombinantly produced TNF receptor or an Fc-fusion protein containing a TNF receptor, an antagonist of TNF, ie a TNF type polypeptide that binds to a receptor that does not cause any signal, or It is a recombinantly produced IL-10 or a mutant thereof that binds to the interleukin-10 receptor and causes a signal at this site. Examples of suitable inhibitors of complement or kallikrein are C1 esterase inhibitors (C1INH) purified or recombinantly produced from human plasma, and mutants thereof having enzyme-inhibitory activity, chemically produced substances with excellent complement-inhibitory effects Phosphorus synthetic complement inhibitors, natural or recombinantly produced aprotinin, or kallikrein-inhibiting mutants, or synthetic kallikrein inhibitors, which are chemically produced substances with excellent kallikrein-inhibiting effects.
안티트롬빈 III(예; 키베르닌R(Kybernin), 베링베르케 아게(Behringwerke AG) 또는 재조합 히루딘(베링베르케 아게)과 C1 에스테라제 억제제(예;베리네르트R(Berinert), 베링베르케 아게)의 배합물이 특히 바람직하다.Antithrombin III (e.g., Kybernin, Behringwerke AG) or recombinant hirudin (beringeber age) and C1 esterase inhibitors (e.g., Berneret R , Bering Particular preference is given to a combination of BERKE AG).
하기 실시예는 본 발명을 더 상세히 설명한다.The following examples illustrate the invention in more detail.
실시예 1Example 1
암컷 CD 래트를 치사량의 엔도톡신(50mg/kg, 정맥내)으로 처리한다. 세 그룹을 형성한 다음, LPS를 투여하기 15분전에 시작하여, 5시간 동안 정맥내 주입(1ml/h)한다. 그룹 1은 생리학적 염화나트륨 용액을 투여하고, 그룹 2는 재조합 히루딘 0.17mg/kg을 투여하며, 그룹 3은 재조합 히루딘 0.17mg/kg×h 및 C1 에스테라제 억제제 100U/kg×h의 복합 치료를 한다. 표 1에 나타낸 바와 같이, 재조합 히루딘은 대조군과 비교하여 생존율을 명백히 연장시키며, C1 에스테라제 억제제를 사용한 복합 치료는 놀랍게도 단독으로 안티트롬빈을 사용한 치료보다 명백하게 우수하다.Female CD rats are treated with lethal doses of endotoxin (50 mg / kg, intravenously). Three groups were formed, followed by intravenous infusion (1 ml / h) for 5 hours, beginning 15 minutes prior to LPS administration. Group 1 is administered physiological sodium chloride solution, Group 2 is administered 0.17 mg / kg recombinant hirudin, Group 3 is a combination of 0.17 mg / kg × h recombinant Hirdin and 100 U / kg × h C1 esterase inhibitor Treat. As shown in Table 1, recombinant hirudin apparently prolongs survival compared to the control, and the combined treatment with C1 esterase inhibitors is surprisingly superior to treatment with antithrombin alone.
표 1Table 1
실시예 2Example 2
실시예 1과 동일한 동물 모델을 사용하여, 두 그룹을 형성한다: 제1 그룹은 사람 혈장으로부터 분리된 트롬빈 억제제 안티트롬빈 III 37.5U/kg×h를 주입하고, 제2 그룹은 추가로 C1 에스테라제 억제제 125U/kg×h를 투여한다. 표 2는 안티트롬빈 III 및 C1INH를 사용한 복합 치료가 안티트롬빈만을 사용하는 단독치료법(monotherapy)보다 우수하다는 것을 나타낸다.Using the same animal model as Example 1, two groups are formed: the first group is injected with thrombin inhibitor antithrombin III 37.5 U / kg × h, isolated from human plasma, and the second group is further C1 ester 125 U / kg × h of inhibitor is administered. Table 2 shows that the combination treatment with antithrombin III and C1INH is superior to monotherapy with antithrombin only.
표 2TABLE 2
결과적으로, 안티트롬빈 III 및 히루딘을 사용한 안티트롬빈 치료법을 패혈증 및 패혈증성 쇼크 예방 및 치료를 위한 다른 성분과 병용할 수 있음을 입증할 수 있다.As a result, it can be demonstrated that antithrombin therapy with antithrombin III and hirudin can be combined with other ingredients for the prevention and treatment of sepsis and septic shock.
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| DE19937656A1 (en) * | 1999-08-13 | 2001-02-15 | Aventis Behring Gmbh | Use of antithrombin III for the prophylaxis and therapy of diseases |
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-
1994
- 1994-05-10 ES ES94107265T patent/ES2172520T3/en not_active Expired - Lifetime
- 1994-05-10 DE DE59410056T patent/DE59410056D1/en not_active Expired - Lifetime
- 1994-05-10 AT AT94107265T patent/ATE213641T1/en active
- 1994-05-10 EP EP94107265A patent/EP0629406B1/en not_active Expired - Lifetime
- 1994-05-23 AU AU63261/94A patent/AU688309B2/en not_active Expired
- 1994-05-24 KR KR1019940011258A patent/KR100352196B1/en not_active IP Right Cessation
- 1994-05-24 CA CA002124161A patent/CA2124161C/en not_active Expired - Fee Related
- 1994-05-24 JP JP10929794A patent/JP3739816B2/en not_active Expired - Fee Related
-
1997
- 1997-01-29 US US08/789,406 patent/US20040214756A1/en not_active Abandoned
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4994367A (en) * | 1988-10-07 | 1991-02-19 | East Carolina University | Extended shelf life platelet preparations and process for preparing the same |
Also Published As
| Publication number | Publication date |
|---|---|
| ES2172520T3 (en) | 2002-10-01 |
| JPH06336440A (en) | 1994-12-06 |
| ATE213641T1 (en) | 2002-03-15 |
| DE59410056D1 (en) | 2002-04-04 |
| AU688309B2 (en) | 1998-03-12 |
| AU6326194A (en) | 1994-12-01 |
| CA2124161C (en) | 2008-11-18 |
| JP3739816B2 (en) | 2006-01-25 |
| EP0629406A1 (en) | 1994-12-21 |
| EP0629406B1 (en) | 2002-02-27 |
| DE4317282A1 (en) | 1994-12-01 |
| US20040214756A1 (en) | 2004-10-28 |
| CA2124161A1 (en) | 1994-11-26 |
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